Poly-4-aminopyrrole-2-carboxamido derivatives and their use as antiuiral or antitumor agents

ABSTRACT

Compound of the formula (I) ##STR1## wherein n is zero or an integer of 1 to 3; 
     R is 
     (a) --NHR 3 , wherein R 3  is 
     (a&#39;) --CON(NO)R 4 , in which R 4  is C 1  -C 4  alkyl either unsubstituted or substituted by halogen; or 
     (b&#39;) --CO(CH 2 ) m  --R 5 , in which R 5  is halogen, oxiranyl, methyloxiranyl, aziridinyl, a group ##STR2##  or a group ##STR3##  and m is zero or an integer of 1 to 4; or (b) ##STR4##  wherein either R 6  and R 7  are the same and are each oxiranemethyl, aziridinemethyl, or C 2  -C 4  alkyl 2-substituted by halogen or by a group --OSO 2  R 8  wherein R 8  is C 1  -C 4  alkyl or phenyl, or one of R 6  and R 7  is hydrogen and the other is as defined above; 
     each group R 1  is, independently, hydrogen or C 1  -C 4  alkyl; 
     R 2  is a C 1  -C 6  alkyl group terminating with (i) a basic moiety chosen from an amino group, a mono- or di- C 1  -C 6  alkylamino group, an amidino group, a group ##STR5##  imidazolyl, imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl; or (ii) a carboxy group; or (iii) a free hydroxy group --OH or a glycosilated hydroxy group --OD wherein D is a glucose, mannose or ribose sugar residue or the daunosamine amino-sugar residue; with the proviso that n is different from one when R 2  is ##STR6##  and the pharmaceutically acceptable salts thereof. The compounds are useful as antiviral and antitumor agents.

The invention relates to poly-4-aminopyrrole-2-carboxamido derivatives,to a process for their preparation and to pharmaceutical compositionscontaining them.

Distamycin A is a well known compound having the following formula##STR7## Literature referring to distamycin A includes, for example,Nature 203, 1064 (1964).

The invention provides distamycin A derivatives having the followinggeneral formula (I) ##STR8## wherein n is zero or an integer of 1 to 3;

R is

(a) --NHR₃, wherein R₃ is

(a') --CON(NO)R₄, in which R₄ is C₁ -C₄ alkyl either unsubstituted orsubstituted by halogen; or

(b') --CO(CH₂)_(m) --R₅, in which R₅ is halogen, oxiranyl,methyloxiranyl, aziridinyl, cyclopropyl or an alicyclic α,β-unsaturatedketone or lactone, and m is zero or an integer of 1 to 4; or

(b) ##STR9## wherein either R₆ and R₇ are the same and are eachoxiranemethyl, aziridinemethyl, or C₂ -C₄ alkyl 2-substituted by halogenor by a group --OSO₂ R₈, wherein R₈ is C₁ -C₄ alkyl or phenyl, or one ofR₆ and R₇ is hydrogen and the other is as defined above;

each group R₁ is, independently, hydrogen or C₁ -C₄ alkyl;

R₂ is a C₁ -C₆ alkyl group terminating with a basic or acidic moiety orwith a free or glycosilated hydroxy group, with the proviso that n isdifferent from one when R₂ is ##STR10##

The invention includes also the pharmaceutically acceptable salts of thecompounds of formula (I) as well as all the possible isomers covered bythe formula (I), both separately and in mixture.

When R₄ is unsubstituted C₁ -C₄ alkyl, methyl and ethyl are preferred,in particular methyl.

When R₄ is C₁ -C₄ alkyl substituted by halogen, the halogen is,preferably, chlorine or bromine; in this case preferred R₄ values arechloroethyl and fluoroethyl.

Preferred n values are zero, 1 and 2.

When R₅ is halogen, it is, preferably, chlorine or bromine.

When R₅ is methyloxiranyl, it may be either 2-methyloxiranyl ##STR11##or 3-methyloxiranyl ##STR12## preferably being 3-methyloxiranyl.

When R₅ is an alicyclic α,β-unsaturated ketone or lactone, it is, e.g.,a group ##STR13## or, respectively, a group ##STR14##

Preferred R₅ values are oxiranyl ##STR15## 1-aziridinyl ##STR16##cyclopropyl ##STR17## a group ##STR18## or a group ##STR19##

Preferred m values are zero, 1 or 2.

A R₆ /R₇ C₂ -C₄ alkyl group 2-substituted by halogen is, preferably,2-chloroethyl.

A R₆ /R₇ C₂ -C₄ alkyl group 2-substituted by a group --OSO₂ R₈ is,preferably, a group --CH₂ --CH₂ --OSO₂ R₈, wherein R₈ is C₁ -C₄ alkyl,preferably methyl.

Preferably each group R₁, independently, is C₁ -C₄ alkyl, in particularmethyl and, most preferably, all groups R₁ are methyl. Subject to theabove proviso, when R₂ is a C₁ -C₆ alkyl group terminating with a basicmoiety, the C₁ -C₆ alkyl is, preferably, C₁ -C₄ alkyl, in particularethyl or n-propyl, and the basic moiety is, for instance, an aminogroup; a mono- or di-C₁ -C₆ alkyl amino group, e.g. di-C₁ -C₄-alkyl-amino; an amidino group; a group ##STR20## or a nitrogencontaining heteromonocyclic ring such as, e.g., imidazolyl,imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl. Preferred R₂ C₁-C₆ alkyl groups terminating with a basic moiety are, subject to theabove proviso, e.g., ##STR21## wherein p is an integer of 1 to 4.

When R₂ is a C₁ -C₆ alkyl group terminating with an acidic moiety, theC₁ -C₆ alkyl is preferably C₁ -C₄ alkyl, in particular ethyl orn-propyl, and the acidic moiety is, preferably, a carboxy group.

Preferred R₂ C₁ -C₆ alkyl group terminating with an acidic moiety is,e.g., a group --(CH₂)_(p) --COOH wherein p is an integer of 1 to 4.

When R₂ is a C₁ -C₆ alkyl group terminating with a free hydroxy group itis, e.g., a group --(CH₂)_(p) --CH₂ OH wherein p is an integer of 1 to4.

When R₂ is a C₁ -C₆ alkyl group terminating with a glycosilated hydroxygroup, it is, e.g., a group --(CH₂)_(p) --CH₂ --O--D wherein p is asdefined above and D is a sugar or amino-sugar residue.

The sugar residue may be, e.g., a glucose, mannose or ribose residue;the amino-sugar residue may be, for instance, daunosamine.

As already said, the invention includes also the pharmaceuticallyacceptable salts of the compounds of formula (I). The salts includesboth the salts with pharmaceutically acceptable acids, either inorganicacids such as, e.g., hydrochloric, hydrobromic, nitric and sulfuric, ororganic acids such as, e.g., citric, tartaric, maleic, fumaric,methanesulfonic and ethanesulfonic, and the salts with pharmaceuticallyacceptable bases, either inorganic bases such as, for instance, alkalimetal, e.g. sodium or potassium, or alkaline-earth metal, e.g. calciumor magnesium, or zinc or aluminium, hydroxides, or organic bases, suchas, e.g., aliphatic amines as methylamine, diethylamine, trimethylamine,ethylamine, and heterocyclic amines as, e.g., piperidine.

Salts of the compounds of formula (I) with acids may be, e.g., the saltsof the compounds of formula (I) wherein R₂ is a C₁ -C₆ alkyl groupterminating with a basic moiety with an acid, e.g. one of thosehereabove specified.

Salts of the compounds of formula (I) with bases may be, e.g., the saltsof the compounds of formula (I) wherein R₂ is a C₁ -C₆ alkyl groupterminating with an acidic moiety with a base, e.g. one of thosehereabove specified.

A preferred class of compounds under this invention is represented bythe compounds of formula (I) wherein, subject to the above proviso,

n is zero, 1 or 2;

R is --NHR₃ wherein R₃ is

(a') --CON(NO)R₄ wherein R₄ is C₁ -C₄ alkyl substituted by halogen, or

(b') --CO(CH₂)_(m) --R₅ wherein R₅ is halogen, oxiranyl, 1-aziridinyl,cyclopropyl, or an alicyclic α,β-unsaturated lactone, and m is zero, 1or 2;

each group R₁ is, independently, C₁ -C₄ alkyl;

R₂ is a C₁ -C₆ alkyl group terminating with a basic moiety, and thesalts thereof with pharmaceutically acceptable acids, in particular withhydrochloric acid.

In the above preferred class a R₄ or R₅ C₁ -C₄ alkyl group is,preferably, methyl or ethyl; a halogen atom is, preferably, chlorine; analicyclic α,β-unsaturated lactone is, preferably, a group ##STR22## a R₁C₁ -C₄ alkyl group is, preferably, methyl; in the R₂ substituent the C₁-C₆ alkyl group is, preferably, C₁ -C₄ alkyl, in particular ethyl orn-propyl, and the basic terminal moiety may be of those previouslyspecified in particular, e.g., a group ##STR23## wherein p is an integerof 1 to 4.

A particularly preferred group of compounds in the ambit of the abovepreferred class are the compounds of formula (I) wherein, subject to theabove proviso,

n is zero, 1 or 2;

R is --NHR₃ wherein R₃ is

(a') a group --CON(NO)R₄ wherein R₄ is --CH₂ --CH₂ --Cl, or

(b') a group --CO(CH₂)_(m) --R₅ wherein either m is 1 or 2 and R₅ ischlorine, or m is zero and R₅ is oxiranyl, 1-aziridinyl or cyclopropyl,or m is 2 and R₅ is ##STR24## each group R₁ is methyl; R₂ is a C₁ -C₄alkyl group with a basic terminal moiety chosen from amino, a di-C₁ -C₄-alkyl-amino group and amidino,

and the salts thereof with pharmaceutically acceptable acids, inparticular hydrochloric acid.

In the hereabove said preferred group of compounds, preferred R₂ valuesare ##STR25## wherein p is an integer of 1 to 4.

Another preferred class of compounds under this invention are thecompounds of formula (I) wherein, subject to the above proviso,

n is zero, 1 or 2;

R is ##STR26## wherein R₆ and R₇ are the same and are eachoxiranemethyl, 1-aziridinemethyl, or a C₂ -C₄ alkyl group 2-substitutedby halogen or by a group --OSO₂ R₈ wherein R₈ is C₁ -C₄ alkyl;

each group R₁ is, independently, C₁ -C₄ alkyl;

R₂ is a C₁ -C₆ alkyl group terminating with a basic moiety,

and the salts thereof with pharmaceutically acceptable acids, inparticular with hydrochloric acid.

In the above preferred class a C₂ -C₄ alkyl group in R₆ /R₇ is,preferably, ethyl; a halogen is, preferably, chlorine; when R₆ and R₇are a C₂ -C₄ alkyl group 2-substituted by halogen, they are, preferably,2-chloroethyl; when R₆ and R₇ are a C₂ -C₄ alkyl 2-substituted by agroup --OSO₂ R₈ where R₈ is C₁ -C₄ alkyl, they are, preferably,methanesulfonyloxyethyl; a C₁ -C₄ alkyl group for R₁ is, preferably,methyl; in the R₂ substituent the C₁ -C₆ alkyl group is, preferably, C₁-C₄ alkyl, in particular ethyl or n-propyl, and the terminal basicmoiety, may be one of those previously specified, e.g., a group##STR27## or a group ##STR28## wherein p is an integer of 1 to 4.

A particularly preferred group of compounds within the hereabove saidpreferred class are the compounds of formula (I) wherein, subject to theabove proviso,

n is zero, 1 or 2;

R is ##STR29## wherein R₆ and R₇ are both oxiranemethyl,1-aziridinemethyl, 2-chloroethyl or methanesulfonyloxyethyl;

each group R₁ is methyl;

R₂ is a C₁ -C₄ alkyl group with a terminal basic moiety chosen fromamino, a di-C₁ -C₄ -alkylamino group and amidino, and the salts thereofwith pharmaceutically acceptable acids, in particular with hydrochloricacid.

In the hereabove said preferred group of compounds preferred R₂ valuesare ##STR30## wherein p is an integer of 1 to 4.

Specific examples of preferred compounds under this invention,especially in the form of salts with hydrochloric acid, are thefollowing:

β-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

β-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-[3-methyl-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-3-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]DistamycinA;

N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-(cyclopropylcarboxamido(pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamide]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamdio]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

β-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;

3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;

N-deformyl-N-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]DistamycinA;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine.

The compounds object of the invention can be prepared by a processcomprising:

(A) reacting a compound of formula (II) ##STR31## wherein R₁, R₂ and nare as defined above, with a compound of formula (III) ##STR32## whereinR₄ is as defined above and Z is a leaving group, so obtaining a compoundof formula (I) wherein R is --NHR₃ and R₃ is --CON(NO)R₄, wherein R₄ isas defined above; or

(B) reacting a compound of formula (II), wherein R₁, R₂ and n are asdefined above, with a compound of formula (IV)

    Z'--CO--(CH.sub.2).sub.m --R.sub.5                         (IV)

wherein

R₅ and m are as defined above and Z' is a leaving group, so obtaining acompound of formula (I) wherein R is --NHR₃ and R₃ is --CO(CH₂)_(m)--R₅, wherein m and R₅ are as defined above; or

(C) reacting a compound of formula (II), wherein R₁, R₂ and n are asdefined above, with a compound of formula (V) ##STR33## wherein X may behydrogen, C₁ -C₂ alkyl or halomethyl, to give a compound of formula (VI)##STR34## wherein R₁, R₂ and n are as defined above and each X has themeaning corresponding to the meaning of X in the compound (V), andtransforming a compound of formula (VI) into a compound of formula (I)wherein R is ##STR35## wherein R₆ and R₇ are as defined above; and, ifdesired, converting a compound of formula (I) into another compound offormula (I) and/or, if desired, salifying a compound of formula (I) orobtaining a free compound from a salt and/or, if desired, separating amixture of isomers of formula (I) into the single isomers.

In the compounds of formula (III) the leaving group Z may be, e.g., anazido group or a trichlorophenoxy or succinimido-N-oxy group.

The reaction between a compound of formula (II) and a compound offormula (III) is preferably carried out in the presence of a solventand, preferably, using an excess of the compound of formula (III), e.g.from about 1.1 to about 2 moles of compound (III) per 1 mole of compound(II). The solvent preferably is an inert organic solvent chosen e.g.from dialkylsulphoxides, e.g. dimethylsulphoxide, aliphatic aciddialkylamides, e.g. dimethylformamide or dimethylacetamide, phosphoricacid triamide or hexamethylphosphoramide, for example, dioxane ordimethoxyethane. Dimethylformamide (DMF) is a particularly preferredsolvent.

The reaction temperature may range from about -10° C. to about 25° C.,although 0° C. is a particularly preferred temperature.

The time required for the reaction may vary within the range from about0.5 to about 6 hours.

The displaceable group Z' in the compound of formula (IV) may be, e.g.,a halogen atom, e.g. chlorine or bromine, or an imidazolyl or phenoxygroup.

The reaction between a compound of formula (II) and a compound offormula (IV) is preferably carried out in the presence of a solvent and,preferably, using an excess of the compound of formula (IV), e.g. fromabout 1.1 to about 2 moles of compound (IV) per 1 mole of compound (II).

The solvent preferably is an inert organic solvent chosen fromdialkylsulfoxides, e.g. dimethylsulfoxides, aliphatic acid dialkylamide,e.g., dimethylformamide, heterocyclic amines like pyridine, aliphaticalcohols and also water.

A particularly preferred solvent is DMF.

The reaction temperature may range from about -50° C. to about 50° C.The time required for the reaction may vary approximately within therange from 0.5 to 24 hours.

When in the compound of formula (V) X is halomethyl, it is preferably,chloromethyl or bromomethyl.

The reaction between a compound of formula (II) and a compound offormula (V) is preferably carried out in the presence of a solvent and,preferably, using an excess of the compound of formula (V), e.g. fromabout 25 moles to about 50 moles of compound (V) per 1 mole of compound(II).

The solvent can be, e.g., water, an aliphatic alcohol, e.g. methanol orethanol, an aliphatic carboxylic acid such as, e.g., acetic acid, analiphatic acid dialkylamide, e.g. dimethylformamide, or adialkylsulphoxide, e.g. dimethylsulphoxide, dioxane or dimethoxyethane.Methanol is a particularly preferred solvent.

The reaction temperature may range from about -20° C. to about 25° C.

The time required for the reaction may vary within the range from about2 to about 48 hours.

The transformation of a compound of formula (VI) into a compound offormula (I) wherein R is a group ##STR36## wherein R₆ and R₇ are aspreviously defined, may be carried out through reactions commonly usedin the organic chemistry.

Thus, for example, a compound of formula (VI) wherein each group X ishydrogen or C₁ -C₂ alkyl may be reacted with an halogenating agent suchas, e.g., an halide, e.g. chlorine or bromine, or a thionyl halide, e.g.thionylchloride, to give a compound of formula (I) wherein R is a group##STR37## wherein each R₆ and R₇ is C₂ -C₄ alkyl 2-substituted byhalogen, e.g. chlorine or bromine. Similarly, a compound of formula (VI)wherein X is hydrogen or C₁ -C₂ alkyl may be reacted with a sulfonicacid of formula R₈ SO₃ H, wherein R₈ is as defined above or, mostpreferably, with a reactive derivative thereof such as, e.g., thecorresponding sulfonyl halide, e.g. chloride, or anhydride, to give acompound of formula (I) wherein R is a group ##STR38## wherein each R₆and R₇ is C₂ -C₄ alkyl 2-substituted by a group --O--SO₂ R₈ wherein R₈is as defined above.

On the other hand, a compound of formula (VI) wherein each group X ishalomethyl, e.g. chloromethyl or bromomethyl may be reacted with a baseto give a compound of formula (I) wherein R is a group ##STR39## whereineach R₆ and R₇ is oxiranemethyl.

The base may be either an inorganic base such as, for instance, analkali metal, e.g. sodium or potassium, hydroxide, or an alkaline-earthmetal, e.g. calcium or magnesium, hydroxide, or an organic base such as,for instance, an aliphatic amine, e.g. trimethylamine, or a heterocyclicamine, e.g. pyridine, piperidine, morpholine or methylmorpholine.

Other compounds of formula (I) wherein R is a group ##STR40## may beprepared from a compound of formula (VI) through reactions well known inthe organic chemistry and following known procedures.

Also the optional conversion of a compound of formula (I) into anothercompound of formula (I), the salification of a compound of formula (I)and the preparation of a free compound from a salt may be carried outaccording to known methods.

Conventional procedures, such as, e.g., fractional crystallization andchromatography, may also be used for the optional separation of amixture of isomers of formula (I) into the single isomers.

The compound of formula (II) can be prepared by following knownprocedures, for example procedures analogous to those described forpreparing distamycin derivatives in Gazz. Chim. Ital. 97, 1110 (1967).

In particular, for example, a compound of formula (II) may be obtainedby the following steps:

(1) reaction of a compound of formula (VII) ##STR41## wherein R₁ and Z'are as defined above, with a compound of formula (VIII)

    H.sub.2 N--R.sub.2                                         (VIII)

wherein

R₁ is as defined above, to obtain a compound of formula (IX) ##STR42##wherein R₁ and R₂ are as defined above;

(2) catalytic hydrogenation of an obtained compound of formula (IX) toobtain a compound of formula (X) ##STR43## wherein R₁ and R₂ are asdefined above;

(3) reaction of a compound of formula (VII) with a compound of formula(X) to obtain a compound of formula (XI) ##STR44## wherein R₁ and R₂ areas defined above; and

(4) catalytic hydrogenation of a compound of formula (XI) to obtain acompound of formula (XII) ##STR45## wherein R₁ and R₂ are as definedabove.

A compound of formula (XII) corresponds to a compound of formula (II)wherein n is zero; in order to obtain a compound of formula (II) whereinn is 1, a compound of formula (XI) can be further processed through thesteps (2) and (3) indicated above and so on.

Compounds of formula (III) are known compounds and they can be prepared,for example, according to J. Med. Chem. (1982), 25, 178-182.

Compounds of formula (IV) and (V) are known compounds too or may beprepared by known methods from known compounds.

In particular, for instance, compounds of formula (IV) are eithercommercial compounds or can be prepared through activation of thecarboxy parent compounds in a conventional way.

Compounds of formula (V) are commercially available compounds.

The compounds of the invention can be used as antiviral andantineoplastic agents.

They show, e.g., a remarkable effectiveness in interfering with thereproductive activity of the pathogenic viruses and protect tissue cellsfrom viral infections. For example they show activity against DNAviruses such as, for instance, Herpes, e.g. Herpex simplex and Herpeszoster, viruses, and Adenoviruses, and against retroviruses such as, forinstance, Sarcoma viruses, e.g., Murine sarcoma virus, and Leukemiaviruses, e.g. Friend leukemia virus.

The compounds of the invention show also cytostatic properties towardstumor cells.

Owing to the above activity the compounds of the invention are able,e.g., to inhibit the growth of various tumors, for instance breastcarcinoma and tumors induced by viruses, e.g. Maloney Sarcoma virus.

The compounds of the invention can be administered by the usual routes,for example parenterally, e.g. by intravenous injection or infusion,intramuscularly, subcutaneously, or also topically.

The dosage depends on the age, weight and conditions of the patient andon the administration route.

For example, a suitable dosage for administration to adult humans mayrange from about 0.1 to about 100 mg pro dose 1-4 times a day.

As already said, the invention includes also pharmaceutical compositionscontaining a compound of formula (I) as the active substance, inassociation with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention are usually preparedfollowing conventional methods and are administered in apharmaceutically suitable form.

For instance, solutions for intravenous injection of infusion maycontain as carrier, for example, sterile water or preferably they may bein the form of sterile aqueous isotonic saline solutions.

Suspensions or solutions for intramuscular injections may containtogether with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride. Inthe forms for topical application, e.g. creams, lotions or pastes foruse in dermatological treatment, the active ingredient may be mixed withconventional oleaginous or emulsifying excipients.

The following examples illustrate but do not limit the invention.

The abbreviations DMF and THF stand for N,N-dimethylformamide and,respectively, tetrahydrofurane.

EXAMPLE 1

To a stirred aqueous solution of N,N-dimethylaminopropylamine (2.03 g in40 ml of water) and sodium bicarbonate (3.36 g) at room temperature asolution of N-methyl-4-n-nitropyrrole-2-carboxylic acid chloride (4 g)in 5 ml of benzene was added. The resulting mixture was stirred for 2hours at room temperature, saturated with sodium chloride and extractedwith benzene (2×50 ml). The dried organic extracts were concentrated invacuo and the residue was crystallized from light petroleum ether toyield 3.5 g of pure3-[N-methyl-4-nitro-pyrrole-2-carboxamido]propyldimethylamine, whiteneedles, m.p. 118°-120° C.

N.M.R. (DMSO-d₆): δ 1.60 (2H, m); 2.12 (6H, s); 3.23 (2H, t); 3.20 (2H,m); 3.88 (3H, s); 7.37 (1H, d); 8.08 (1H, bd); 8.35 (1H, bt).

EXAMPLE 2

The compound of example 1 (3.4 g) was dissolved in ethanol (40 ml) anddiluted hydrochloric acid (20 ml) and reduced over a Pd catalyst (5% oncarbon) under H₂ pressure (50 psi) in a Parr apparatus. Water (20 ml)was added and the catalyst filtered off. The resulting solution wasconcentrated and the residue was dissolved in water (40 ml). Sodiumbicarbonate (4 g) was added, followed by a solution ofN-methyl-4-nitropyrrole-2-carboxylic acid chloride (2.8 g) in 20 ml ofbenzene. The resulting mixture was stirred for about 2 hours at roomtemperature and then was extracted with chloroform. The dried organicextracts were concentrated in vacuo and the residue was purified bycolumn chromatography (CHCl₃ 75, EtOH_(95%) 25, NH₄ OH 0.6) to give 4.7g of3-[N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole-2-carboxamido]propyl-dimethylamineas a yellow solid, m.p. 178°-180° C.

N.M.R. (CDCl₃) δ: 1.74 (2H, m); 2.30 (6H, s); 2.49 (2H, t); 3.44 (2H,m); 3.88 (3H, s); 3.99 (3H, s); 6.58 (1H, d); 7.21 (1H, d); 7.38 (1H,d); 7.6 (1H, br); 8.80 (1H, bs).

By analogous procedure, the following compounds were obtained:

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine,m.p. 175° C. (dec.);

N.M.R. (DMSO-d₆) δ: 1.63 (2H, m); 2.22 (6H, s); 2.38 (2H, t); 3.16 (2H,dt); 3.80 (3H, s); 3.85 (3H, s); 3.87 (3H, s); 3.97 (3H, s); 6.80-7,30(6H, m); 7.59 (1H, d); 8.04 (1H, t); 8.16 (1H, d); 9.84 (1H, bs); 9.95(1H, bs); 10.26 (1H, bs);

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine,m.p. 195° C. (dec.);

N.M.R. (DMSO-d₆) δ: 1.64 (2H, m); 2.13 (6H, s); 2.27 (2H, t); 3.20 (2H,dt); 3.80 (3H, s); 3.85 (3H, s); 3.88 (3H, s); 3.98 (3H, s); 6.82 (1H,d); 7.04 (2H, m); 7.18 (1H, d); 7.26 (2H, d); 7.58 (1H, d); 8.18 (1H,d); 8.02 (1H, t); 9.86 (1H, s); 9.94 (1H, s); 10.25 (1H, s);

β-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

β-[N-methyl-4-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

β-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

EXAMPLE 3

β-N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride (900 mg) dissolved in 150 ml of ethanol, 75 ml of waterand 9 ml of 2N HCl was hydrogenated in a Parr apparatus for 45 minutesat 45 psi of H₂ at room temperature over a Pd catalyst (10% on carbon).The catalyst was filtered off and the filtrate were evaporated undervacuum to yield 930 mg of crudeβ-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride. The residue was dissolved in methyl alcohol (60 ml),cooled to -20° C. and heated with 12 ml of ethylene oxide. After 15minutes the temperature was allowed to rise and the mixture is left atroom temperature overnight. The solution was evaporated to drynessaffording, after chromatography on SiO₂ washed with HCl, 800 mg of pureβ-[N-methyl-4-[N-methyl-4-[N,N-bis-(2-hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2carboxamido]propionamidinehydrochloride;

Mass spectrum: m/e 419 (M⁺); 420 (M⁺ +1);

¹ H-N.M.R. (dimethyl-d₆ sulfoxide), δ: 2.63 (2H, t); 2.90-3.80 (10H, m);4.55 (2H, br); 6.30 (1H, d); 6.52 (1H, d); 6.92 (1H, d); 7.12 (1H, d);8.20 (1H, t); 8.70 (2H, bs); 9.01 (2H, bs); 9.63 (1H, s);

U.V. (EtOH 95%): λ max 245, ε=16,352; λ max 292, ε=15,070.

By analogous procedure the following compounds were obtained:

N-deformyl-N-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2-carboxamido]DistamycinA hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyldimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride.

EXAMPLE 4

A stirred solution ofβ-[N-methyl-4-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride (717 mg) in dry pyridine (10 ml) was cooled with an icebath, treated under nitrogen atmosphere with a solution ofmethansulphonylchloride in pyridine (1.27M, 2.7 ml) and stirred at 5° C.for 45 minutes. After quenching with methyl alcohol, the whole wasallowed to warm to room temperature and evaporated to dryness. The crudeproduct was chromatographed on silica yielding 440 mg ofβ-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

¹ H-NMR (dimethyl-d₆ sulfoxide), δ 2.63 (t, 2H); 3.30-3.80 (m, 10H);3.78 (s, 3H); 3.81 (s, 3H); 6.42 (d, 1H); 6.55 (d, 1H); 6.92 (d, 1H);7.17 (d, 1H); 8.20 (t, 1H); 8.70 (bs, 2H); 9.02 (bs, 2H); 9.68 (s, 1H);U.V. (EtOH 95%): λmax 245, ε=17,373; λmax 293, ε=15,450.

By analagous procedure the following compounds were obtained:

N-deformyl-N-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dymethylaminehydrochloride.

3-[N-methyl-4-[N-methyl-4-[N-methyl-4[N-methyl-4[N,N-bis(2-chloroethylamino]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride.

EXAMPLE 5

To an ice-cooled solution ofβ-[N-methyl-4-(N-methyl-4-aminopyrrole-2-carboxamido)pyrrole-2-carboxamido]propionamidinedihydrochloride (0.404 g) in 5 ml of DMF and 320 mg of2,4,5-trichlorophenyl-N-methyl-N-nitrosocarbamate [prepared according toJ. Med. Chem. 25, 178 (1982)], a solution of diisopropylethylamine(0.164 ml) in 8 ml of DMF was added dropwise. The resulting solution wasstirred 1 hour at 0° C. The reaction mixture was concentrated undervacuum and the residue was purified by column chromatography to yield251 mg of β-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride.

    ______________________________________                                        U.V.(EtOH 95%)                                                                        λmax                                                                         ε                                                       ______________________________________                                                241   21,611                                                                  293   28,207                                                          ______________________________________                                    

I.R. (KBr): νcm⁻¹ 3500-2800; 2500-2200; 1450; 970; 650.

N.M.R. (DMS0-d₆) δ: 2.59 (2H, m); 3.15 (3H, s); 3.48 (2H, m); 3.79 (3H,s); 3.85 (3H, s); 7.01-7.31 (4H, m); 8.61 (2H, br); 8.97 (2H, br); 9.91(2H, b); 10.61 (1H, bs).

By analogous procedure the following compounds were obtained:

β-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]-pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-[3-methyl-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-3-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N-deformyl-N-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]DistamycinA.hydrochloride;

N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]DistamycinA. hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N.M.R. (DMSO-d₆ /CDCl₃) δ: 1.90 (2H, m); 2.60 (6H, s); 2.85 (2H, t);3.15-4.00 (6H, m); 4.22 (2H, t); 6.80-7.30 (8H, m); 8.00 (1H, t); 9.63(1H, bs); 9.70 (1H, s); 9.77 (1H, s); 10.48 (1H, s);

β-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine.

EXAMPLE 6 To a solution of (2R,3R)-3-methyl-orixane-carboxylic acid (765mg) in dry THF (20 ml), cooled to -20° C., N-methylmorpholine (0.825 ml)and than pivaloyl chloride (0.920 ml) were added. The resultingsuspension was stirred at -20° C. for 20 minutes, then the whole wasadded to a cooled solution of 2.6 g of3-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminodihydrochloride in DMF (50 ml) and NaHCO₃ (0.4 g). The mixture wasstirred for 30 minutes at 0° C., and then for 4 hours at roomtemperature. Solvents were evaporated in vacuum to dryness, and theresidue chromatographed on SiO₂ (solvent CHCl₃ 100/CH₃ OH100/HCl_(2N) 1) to yield 1.4 g of3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[3-methyl-(2R,3R)oxiranecarboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminohydrochloride.

N.M.R. (DMSO-d₆) δ: 1.25 (3H, d); 3.3 (1H, m); 3.60 (1H, d); [J=4.7H₂(cis)].

By analogous procedure the following compounds were obtained:

N-deformyl-N-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

β-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N-deformyl-N-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

β-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N-deformyl-N-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

β-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N-deformyl-N-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

β-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride;

3-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido[pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride;

N-deformyl-N-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]DistamycinA.hydrochloride;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminehydrochloride.

We claim:
 1. A compound of formula (I) ##STR46## wherein n is zero or aninteger of 1 to 3;R is(a) --NHR₃, wherein R₃ is(a') --CON(NO)R₄, inwhich R₄ is C₁ -C₄ alkyl either unsubstituted or substituted by halogen;or (b') --CO(CH₂)_(m) --R₅, in which R₅ is halogen, oxiranyl,methyloxiranyl, aziridinyl, a group ##STR47## or a group ##STR48## and mis zero or an integer of 1 to 4; or (b) ##STR49## wherein either R₆ andR₇ are the same and are each oxiranemethyl, aziridinemethyl, or C₂ -C₄alkyl 2-substituted by halogen or by a group --OSO₂ R₈ wherein R₈ isC_(1-C) ₄ alkyl or phenyl, or one of R₆ and R₇ is hydrogen and the otheris as defined above; each group R₁ is, independently, hydrogen or C₁ -C₄alkyl; R₂ is a C₁ -C₆ alkyl group terminating with (i) a basic moietychosen from an amino group, a mono- or di-C₁ -C₆ alkylamino group, anamidino group, a group ##STR50## imidazolyl, imidazolinyl,tetrahydropyrimidinyl and oxazolidinyl; or (ii) a carboxy group; or(iii) a free hydroxy group --OH or a glycosilated hydroxy group --ODwherein D is a glucose, mannose or ribose sugar moiety or thedaunosamine aminosugar moiety with the proviso that n is different fromone when R₂ is ##STR51## and the pharmaceutically acceptable saltsthereof.
 2. A compound of formula (I), according to claim 1 wherein,subject to the proviso of claim 1,n is zero, 1 or 2; R is --NHR₃ whereinR₃ is(a') --CON(NO)R₄ wherein R₄ is C₁ -C₄ alkyl substituted by halogenor (b') --CO(CH₂)_(m) --R₅ wherein R₅ is halogen, oxyranyl,1-aziridinyl, a group ##STR52## or a group ##STR53## and m is zero, 1 or2; each group R₁ is, independently, C₁ -C₄ alkyl; R₂ is a C₁ -C₆ alkylgroup terminating with a basic moiety chosen from an amino group, amono- or di-C₁ -C₆ alkyl-amino group; an amidino group, a group##STR54## or a nitrogen containing heteromonocyclic ring selected fromthe group consisting of imidazolyl, imidazolinyl, tetrahydropyrimidinyland oxazolidinyl, and the salts thereof with pharmaceutically acceptableacids.
 3. A compound of formula (I), according to claim 1 wherein,subject to the proviso of claim 1,n is zero, 1 or 2; R is ##STR55##wherein R₆ and R₇ are the same and are each oxiranemethyl,1-aziridinemethyl, or a C₂ -C₄ alkyl group 2-substituted by halogen orby a group --OSO₂ R₈ wherein R₈ is C₁ -C₄ alkyl;each group R₁ is,independently, C₁ -C₄ alkyl; R₂ is a C₁ -C₆ alkyl group terminating witha basic moiety chosen from an amino group, a mono- or a di-C₁ -C₆alkylamino group, an amidino group, a group ##STR56## or a nitrogencontaining heteromonocyclic ring selected from the group consisting ofimidazolyl, imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl, andthe salts thereof with pharmaceutically acceptable acids.
 4. A compoundof formula (I) as defined in claim 1 selected from the group consistingof:β-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;β-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-[3-methyl-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-3-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]DistamycinA;N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4[3-(2-chloroethyl)-3-nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;β-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;β-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;β-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;β-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;β-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;N-deformyl-N-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]DistamycinA;3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine.5. A hydrochloric acid salt of a compound of formula (I) as claimed inclaim
 4. 6. An antiviral or antitumor pharmaceutical compositioncontaining a suitable carrier and/or diluent and, as an active principlean effective amount of a compound of formula (I) according to claim 1 ora pharmaceutically acceptable salt thereof.